Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

An oral dosage form of entacapone and methods for the preparation thereof
are provided.

Claims:

1. An oral dosage form comprising a pharmacologically effective amount of
entacapone as the sole drug substance, wherein the amount of entacapone
in a portion of the oral dosage form is from 35% to 99% by weight of the
portion.

2-43. (canceled)

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to an oral dosage form of entacapone
and to the methods that may be used in the preparation thereof.

BACKGROUND OF THE INVENTION

[0002] Entacapone,
((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-diethyl-2 propenamide), is
a catechol-O-methyl transferase (COMT) inhibitor that is used in
combination with levodopa and a dopa decarboxylase (DDC) inhibitor to
treat Parkinson's disease (PD). It is commercially available as a
stand-alone formulation under the trademarks Comtess® and Comtan®
and under trademark Stalevo® as a fixed combination
(levodopa:carbidopa:entacapone: 50 mg:12.5 mg:200 mg, 100 mg:25 mg:200 mg
and 150 mg:37.5 mg:200 mg).

[0003] Special attention is required when managing the symptoms of late
stage PD patients who experience severe on-off fluctuations. Doctors
usually prescribe them the stand-alone dosage form due to its flexibility
in dosing. Those patients, especially the ones having swallowing
problems, would benefit if a smaller dosage form would be available.

[0005] Applicants have discovered that it is possible to make an oral
dosage form of entacapone that is more easily swallowed while maintaining
the oral bioavailability of entacapone.

[0006] It is one aspect of the invention to provide an oral dosage form
comprising a pharmacologically effective amount of entacapone as the sole
drug substance, wherein the amount of entacapone in a portion of the oral
dosage form is from 35% to 99%, for instance from 48% to 85%, for
instance from 50% to 65 by weight of the portion.

[0007] It is a further aspect of the invention to provide a tablet
comprising a pharmacologically effective amount of entacapone as the sole
drug substance.

[0008] It is a further aspect of the invention to provide a core tablet
comprising a pharmacologically effective amount of entacapone as the sole
drug substance.

[0009] It is a further aspect of the invention to provide granules
comprising a pharmacologically effective amount of entacapone as the sole
drug substance.

[0010] It is a further aspect of the invention to provide a granule
mixture comprising granules having a pharmacologically effective amount
of entacapone as the sole drug substance, and one or more extragranular
excipients.

[0011] It is a further aspect of the invention to provide a capsule
comprising a pharmacologically effective amount of entacapone as the sole
drug substance.

[0012] It is a further aspect of the invention to provide a kit comprising
the dosage form according to the invention in combination with a dopamine
precursor, such as levodopa, and a dopa decarboxylase inhibitor, for
example carbidopa or benserazide, optionally with other drug substances,
for example MAO B inhibitors.

[0013] It is a further aspect of the invention to provide a method of
treating any condition wherein COMT inhibitors are found to be useful,
particularly conditions wherein levodopa potentiation is needed, for
example Parkinson's disease and restless legs syndrome (RLS, a condition
characterized by an irresistible urge to move the legs, accompanied by
other unpleasant sensations deep within the legs).

[0014] Additional aspects and advantages of the invention will be set
forth in part in the description which follows, and in part will be
obvious from the description, or may be learned by the practice of the
invention. The objects and the advantages of the invention will be
realized and attained by means of the elements and combinations
particularly pointed out in the appended claims.

[0015] It is to be understood that both the foregoing general description
and the following detailed description are exemplary and explanatory only
and do not restrict the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 shows the photographs of the present stand-alone tablet on
the market (sold under the trademarks Comtess® and Comtan®) and a
tablet according to the invention, respectively.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention relates to a new dosage form of entacapone that not
only satisfies the requirements of the patients (such as those who have
symptoms of late stage Parkinson's Disease with severe on-off
fluctuations and patients having difficulty with swallowing), but also
allows simple and cost-effective manufacturing without compromising the
technical quality of the product.

[0018] The preparation of pharmaceutical compositions of entacapone has
proved to be problematic. Entacapone is quickly absorbed in the
gastrointestinal tract, however, the water solubility of entacapone is
very low. Due to the poor solubility, the dissolution rate of entacapone
can be a limiting factor for the absorption of entacapone in the
gastro-intestinal tract. The applicants have found that, in order to
facilitate the absorption to the patient, entacapone having a certain
reduced particle size as discussed below is preferably used in the dosage
forms of the invention.

[0019] Entacapone particles of reduced particle size, however, have tended
to cause manufacturing problems, thereby bringing about unnecessary
delays in production. Potential problems related to reduced particle size
include poor flowability and agglomeration which may result in
compromised content uniformity (i.e. a reproducible amount of entacapone
between different units).

[0020] As a solution to this problem, an oral dosage form of entacapone as
well as methods for the preparation thereof has been invented by the
applicants, which reduces or avoids the manufacturing problems such as
those described above and improves the content uniformity while reducing
the size of the final dosage form.

[0021] In one embodiment of the invention an oral dosage form is provided
comprising a pharmacologically effective amount of entacapone as the sole
drug substance, wherein the amount of entacapone in a portion of the oral
dosage form is from 35% to 99% by weight of the portion.

[0022] In one embodiment of the invention an oral dosage form is provided
comprising a pharmacologically effective amount of entacapone as the sole
drug substance in a portion of the oral dosage form from 48% to 85% by
weight of the portion.

[0023] In one embodiment of the invention an oral dosage form is provided
comprising a pharmacologically effective amount of entacapone as the sole
drug substance in a portion of the oral dosage form from 50% to 65% by
weight of the portion.

[0024] The term "portion" of a dosage form can represent, for example, the
dosage form excluding any outer coating made of pharmaceutically
acceptable excipients. The term "portion" of a dosage form can also
represent, for example, the dosage form excluding any capsule shell that
contains the remainder of the dosage form.

[0025] Thus, where the dosage form is a core tablet, a "portion" of the
dosage form can represent, for example, the entire dosage form. Where the
dosage form is a tablet comprising a core tablet coated with
pharmaceutically acceptable excipients, a "portion" of the dosage form
can represent, for example, the tablet excluding the coating made of
pharmaceutically acceptable excipients. Where the dosage form is a
capsule, a "portion" of the dosage form can represent, for example, the
contents enclosed by the capsule shell.

[0026] Reference to entacapone as "the sole drug substance" indicates that
no other substance is present in a pharmacologically effective amount.

[0027] In one embodiment of the invention an oral dosage form is provided
comprising a pharmacologically effective amount of entacapone as the sole
drug substance, wherein entacapone is in particulate form, at least 90%
of entacapone particles having a diameter less than 55 μm, for
instance at least 90% of particles having a diameter less than 35 μm.
The particle size distribution by volume is measured using Laser
Diffraction Particle sizing (LPD) by adding 1 mg of entacapone and 5 ml
of hexadecane into a 5 ml beaker in ambient conditions and dispensing in
an ultrasonic bath (Decon FS300, Decon Laboratories Ltd. U.K.) for 60
seconds and measuring the sample using the Malvern droplet and particle
size analyser (2600C, model 2805LO, Malvern Instruments Ltd., U.K.)
having a lens with the focal length of 63 mm. The percent values are
calculated from the mean cumulative volume size curve using the Malvern
2600 software version B.22.

[0028] In one embodiment of the invention at least 90% of entacapone
particles have a diameter less than 35 μm.

[0029] In one embodiment of the invention not more than 20% of entacapone
particles have a diameter less than 2 μm.

[0030] In one embodiment of the invention an oral dosage form comprising
entacapone as the sole drug substance is provided allowing at least 50%
of entacapone to be released within the first 30 minutes in a dissolution
test (Apparatus 2 (USP), paddles at 50 rpm, pH 5.5) from said dosage
form.

[0031] In one embodiment of the invention an oral dosage form comprising
entacapone as sole drug substance is provided allowing at least 60% of
entacapone to be released within the first 45 minutes in a dissolution
test (Apparatus 2 (USP), paddles at 50 rpm, pH 5.5) from said dosage
form.

[0032] The oral dosage form according to the invention may be a tablet, a
core tablet, a capsule or the like.

[0034] In one embodiment of the invention the amount of the binder in a
portion of the oral dosage form is from 0.5% to 64.5%, for instance from
1% to 35% by weight of the portion.

[0035] In one embodiment the binder is one or more of povidone,
hypromellose, hydroxypropyl cellulose, methylcellulose and gelatine.

[0036] In one embodiment the binder is povidone. In one embodiment the
binder is povidone and the amount of the binder in a portion of the oral
dosage form is from 0.5% to 8%, for instance from 3% to 6% by weight of
the portion.

[0038] In one embodiment of the invention the hot melt binder is
polyethylene glycol. In one embodiment of the invention the hot melt
binder is polyethylene glycol and the amount of the hot melt binder in a
portion of the oral dosage form is from 15% to 65%, for instance from 25%
to 30% by weight of the portion.

[0039] The dosage form according to the invention may further include, for
instance one or more of disintegrants, fillers, solubility enhancers,
glidants, lubricants (if applicable, for example, if tabletting) as well
as other pharmaceutical excipients.

[0041] In one embodiment of the invention the amount of the disintegrant
in a portion of the oral dosage form is from 0.5% to 64.5%, for instance
from 2% to 40% by weight of the portion.

[0042] In one embodiment the disintegrant is one or more of croscarmellose
sodium, crospovidone, low substituted hydroxypropyl cellulose,
microcrystalline cellulose and sodium starch glycolate.

[0043] In one embodiment the disintegrant is croscarmellose sodium. In one
embodiment the disintegrant is croscarmellose sodium and the amount of
the disintegrant in a portion of the oral dosage form is from is 0.5% to
35%, for instance from 18% to 27%, for instance from 20% to 25% by weight
of the portion.

[0044] In one embodiment, the disintegrant is microcrystalline cellulose.
In one embodiment, the disintegrant is microcrystalline cellulose and the
amount of microcrystalline cellulose in a portion of the oral dosage form
is from 0.5% to 64.0%, for instance from 5% to 20% by weight of the
portion.

[0045] In one embodiment the disintegrant comprises croscarmellose sodium
and microcrystalline cellulose, and the proportion of croscarmellose
sodium to microcrystalline cellulose is from 0.5:99.5 to 99.5:0.5 by
weight, for instance from 40:60 to 80:20 by weight in a portion of the
oral dosage form.

[0046] In one embodiment the disintegrant is low substituted hydroxypropyl
cellulose (L-HPC). In one embodiment the disintegrant is low substituted
hydroxypropyl cellulose and the amount of the disintegrant in a portion
of the oral dosage form is from is 0.5% to 40%, for instance from 15% to
35% by weight of the portion.

[0054] In one embodiment, the lubricant is one or more of glyceryl
behenate, magnesium stearate, sodium lauryl sulphate and sucrose
stearate.

[0055] In one embodiment the lubricant is magnesium stearate. In one
embodiment the lubricant is magnesium stearate and the amount magnesium
stearate in a portion of the oral dosage form is from 0.1% to 3% by
weight of the portion.

[0056] In one embodiment of the invention the dosage form is a coated
tablet. In one embodiment of the invention the tablet is coated, for
instance with a cellulose derivative or polyvinyl alcohol based coating,
polyethylene glycols, acrylate polymers or sugar coating or mixtures
thereof. Preferably, a water based coating is used.

[0057] In one embodiment of the invention the coating comprises dyes,
colour lakes, or pigments, such as iron oxides, for instance yellow or
red irons oxides and titanium dioxide.

[0058] In one embodiment of the invention the dosage form is a coated
tablet and the weight of the tablet coating is from 0.5 to 10% compared
with the weight of the core tablet, for instance from 1 to 4% compared
with the weight of the core tablet.

[0059] In one embodiment of the invention an oral dosage form is provided
comprising entacapone as the sole drug substance and a disintegrant,
wherein the amount of entacapone in a portion of the oral dosage form is
from 35% to 99%, for example from 48% to 85%, for example from 50% to 65%
by weight of the portion and the amount of the disintegrant is from 0.5%
to 64.5%, for example from 2% to 40% by weight of the portion.

[0060] In one embodiment of the invention an oral dosage form is provided
comprising entacapone as the sole drug substance, a disintegrant and a
binder, wherein the amount of entacapone in a portion of the oral dosage
form is from 35% to 99%, for example from 48% to 85%, for example from
50% to 65% by weight of the portion and the amount of the disintegrant is
from 0.5% to 64.5%, for example from 2% to 40% by weight of the portion
and the amount of the binder is from 0.5% to 64.5%, for instance from 1%
to 35% by weight of the portion.

[0061] In one embodiment of the invention an oral dosage form is provided
comprising entacapone as the sole drug substance and croscarmellose
sodium, wherein the amount of entacapone in a portion of the oral dosage
form is from 35% to 99%, for example from 48% to 85%, for example from
50% to 65% by weight of the portion and the amount of croscarmellose
sodium is from 0.5% to 35%, for example from 18% to 27%, for example from
20% to 25% by weight of the portion.

[0062] In one embodiment of the invention an oral dosage form is provided
comprising entacapone as the sole drug substance, croscarmellose sodium
and povidone, wherein the amount of entacapone in a portion of the oral
dosage form is from 35% to 99%, for example from 48% to 85%, for example
from 50% to 65% by weight of the portion, the amount of croscarmellose
sodium is from 0.5% to 35%, for example from 18% to 27%, for example from
20% to 25% by weight of the portion and the amount of povidone is from
0.5% to 8%, for example from 3% to 6% by weight of the portion.

[0063] In one embodiment of the invention an oral dosage form is provided
comprising entacapone as the sole drug substance, croscarmellose sodium,
microcrystalline cellulose and povidone, wherein the amount of entacapone
in a portion of the oral dosage form is from 35% to 99%, for example from
48% to 85%, for example from 50% to 65% by weight of the portion, the
amount of croscarmellose sodium is from 0.5% to 35%, for example from 18%
to 27%, for example from 20% to 25% by weight of the portion, the amount
of microcrystalline cellulose is from 0.5% to 64.0%, for instance from 5%
to 20% by weight of the portion and the amount of povidone is from 0.5%
to 8%, for example from 3% to 6% by weight of the portion.

[0064] In one embodiment of the invention a tablet comprising 200 mg of
entacapone as the sole drug substance is provided having the following
dimensions when measured at the outermost dimensions of the tablet:

length from 11 mm to 16 mm, for instance from 13 mm to 15 mm width from 4
mm to 9 mm, for instance from 6 mm to 8 mm height from 4 mm to 7 mm, for
instance from 4 mm to 6 mm.

[0065] In one embodiment of the invention the tablet is oval. In another
embodiment of the invention the tablet is round.

[0066] In one embodiment of the invention a tablet is provided comprising
entacapone as the sole drug substance and croscarmellose sodium, wherein
the amount of entacapone in a portion of the oral dosage form is from 35%
to 99%, for example from 48% to 85%, for example from 50% to 65% by
weight of the portion and the amount of croscarmellose sodium is from
0.5% to 35%, for example from 18% to 27%, for example from 20% to 25% by
weight of the portion.

[0067] In one embodiment of the invention a tablet is provided comprising
entacapone as the sole drug substance, croscarmellose sodium and
povidone, wherein the amount of entacapone in a portion of the oral
dosage form is from 35% to 99%, for example from 48% to 85%, for example
from 50% to 65% by weight of the portion, the amount of croscarmellose
sodium is from 0.5% to 35%, for example from 18% to 27%, for example from
20% to 25% by weight of the portion and the amount of povidone is from
0.5% to 8%, for example from 3% to 6% by weight of the portion.

[0068] In one embodiment of the invention a tablet is provided comprising
entacapone as the sole drug substance, croscarmellose sodium,
microcrystalline cellulose and povidone, wherein the amount of entacapone
in a portion of the oral dosage form is from 35% to 99%, for example from
48% to 85%, for example from 50% to 65% by weight of the portion, the
amount of croscarmellose sodium is from 0.5% to 35%, for example from 18%
to 27%, for example from 20% to 25% by weight of the portion, the amount
of microcrystalline cellulose is from 0.5% to 64.0%, for instance from 5%
to 20% by weight of the portion and the amount of povidone is from 0.5%
to 8%, for example from 3% to 6% by weight of the portion.

[0069] In one embodiment of the invention a tablet is provided comprising
entacapone as the sole drug substance, croscarmellose sodium,
microcrystalline cellulose, povidone and magnesium stearate, wherein the
amount of entacapone in a portion of the oral dosage form is from 35% to
99%, for example from 48% to 85%, for example from 50% to 65% by weight
of the portion, the amount of croscarmellose sodium is from 0.5% to 35%,
for example from 18% to 27%, for example from 20% to 25% by weight of the
portion, the amount of microcrystalline cellulose is from 0.5% to 64.0%,
for instance from 5% to 20% by weight of the portion, the amount of
povidone is from 0.5% to 8%, for example from 3% to 6% by weight of the
portion and the amount of magnesium stearate is from 0.1% to 3% by weight
of the portion.

[0070] In one embodiment of the invention a tablet is provided comprising
entacapone as the sole drug substance, croscarmellose sodium,
microcrystalline cellulose, povidone, magnesium stearate and a film
coating, wherein the amount of entacapone in a portion of the oral dosage
form is from 35% to 99%, for example from 48% to 85%, for example from
50% to 65% by weight of the portion, the amount of croscarmellose sodium
is from 0.5% to 35%, for example from 18% to 27%, for example from 20% to
25% by weight of the portion, the amount of microcrystalline cellulose is
from 0.5% to 64.0%, for instance from 5% to 20% by weight of the portion,
the amount of povidone is from 0.5% to 8%, for example from 3% to 6% by
weight of the portion, the amount of magnesium stearate is from 0.1% to
3% by weight of the portion and the amount of the coating is from 0.1% to
10%, for example from 1% to 4% by weight of the total dosage form.

[0071] In one embodiment granules comprising a pharmacologically effective
amount of entacapone as the sole drug substance are provided having the
following granule size distribution by volume: the 10% fractile is, for
instance from 7 μm to 60 μm, for instance from 10 μm to 40 μm
and the 90% fractile is, for instance from 600 μm to 1200 μm, for
instance from 750 μm to 1100 μm and the median is, for instance
from 80 μm to 600 μm, for instance from 100 μm to 300 μm. The
granule size distribution by volume is measured using laser diffraction
with dry dispersion (Laser Diffraction Particle Size Analyzer LS13320,
Beckman Coulter Inc., USA). The analysis is carried out in ambient
conditions. The samples are dispersed in air using Tornado Dry Powder
System. The dispersion pressure is 19 inches H2O and the sample amount is
20 ml. The percent values are calculated from the mean cumulative volume
size curve using the Beckman Coulter LS13320 software version 4.21.

[0072] In one embodiment of the invention granules are provided having a
water activity from 0.10 to 0.65, for instance from 0.2 to 0.4 (measured
by the equipment sold under the tradename Aqualab®).

[0073] In one embodiment a granule mixture is provided comprising the
granules described herein above and one or more extragranular excipients.

[0074] In one embodiment a hard gelatine capsule is provided comprising
the granules or the granule mixture according to the invention.

[0075] In one embodiment of the invention the hard gelatine capsule
comprising the granules or the granule mixture has a capsule shell size
from 2 to 00, for example from 1 to 0.

[0076] In one embodiment of the invention a kit is provided comprising the
dosage form according to the invention in combination with a dopamine
precursor, such as levodopa, and a dopa decarboxylase inhibitor, for
example carbidopa or benserazide, optionally with other drug substances,
for example MAO B inhibitors. The dosage forms in the kit may be provided
for sequential or simultaneous administration.

[0077] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with a
binder and optionally one or more other excipients and granulating with a
granulating liquid; or granulating entacapone together with one or more
optional other excipients with a granulating liquid comprising a binder
or by melt granulation; (ii) drying or cooling, respectively and
optionally screening the granules of step (i), optionally bringing the
granules into contact with one or more extragranular excipients and (iii)
compressing the granules and the optional extragranular excipients into a
core tablet.

[0078] It is typical to divide the granulation in three steps: 1)
premixing step 2) addition of the granulation liquid and 3) the so called
kneading step. In many cases, steps 2 and 3 are combined. However, it is
to be understood that it is also possible to carry out all three steps
concurrently.

[0079] In one embodiment of the invention the preparation of the mixture
of entacapone and the binder and/or optional other excipients is
conducted, for instance by diffusion blending (tumble), convection
mixing, for example in a high shear mixer or a single pot processor, or
using continuous granulation, for example in a twin screw mixer.

[0080] Process conditions for a commercial scale (1.0-1.5 m3)
vertical high shear mixer during the premixing step may be the following:
mixing time from 0.5 to 5.5 min, for instance from 1 to 3 min, impeller
rate from 50 to 200 rpm, for instance from 80 to 120 rpm and chopper rate
from 0 to 800 rpm.

[0081] In one embodiment of the invention the granulation step is carried
out in e.g. in a high shear mixer, a single pot processor or by using
continuous granulation.

[0082] Process conditions for a commercial scale vertical high shear mixer
during the addition of water based granulation liquid may be the
following: mixing time from 5 to 20 min, for example from 8 to 16 min.,
impeller rate from 50 to 200 rpm, for instance from 80 to 120 rpm and
chopper rate from 0 to 800 rpm.

[0083] Process conditions for a commercial scale vertical high shear mixer
during the kneading step may be the following: mixing time from 0.5 to 15
min, for example from 2 to 8 min., impeller rate from 50 to 200 rpm, for
instance from 80 to 120 rpm and chopper rate from 0 to 800 rpm.

[0084] In one embodiment of the invention the proportion of the binder to
the granulation mass is from 0.5:99.5 to 64.5:35.5, for example from 1:99
to 35:65 by dry weight.

[0085] In one embodiment of the invention the binder is one or more of
povidone, hypromellose, hydroxypropyl cellulose, methylcellulose and
gelatine.

[0086] In one embodiment of the invention the solvent used in the
granulating liquid is water, a lower alcohol such as ethanol, isopropanol
or a mixture thereof.

[0087] In one embodiment of the invention the granulation liquid is water.
In one embodiment of the invention the granulation liquid is water and
the disintegrant is croscarmellose sodium and the amount of water added
during granulation is from 50% to 120%, for example from 70% to 100%
compared with the dry weight of the granulation mass. It has been found
that using said amounts of water improves flowability and compactibility.

[0088] In one embodiment of the invention the granulation liquid is water
and the disintegrant is L-HPC and the amount of water added during
granulation is from 30% to 100%, for example from 40% to 80% compared
with the dry weight of the granulation mass.

[0089] In one embodiment of the invention the granulation liquid is a
dispersion or suspension.

[0090] In one embodiment of the invention the granules are dried, for
instance in a single pot processor, in a fluidized bed or in a drying
chamber.

[0091] In one embodiment of the invention the granules are dried directly
in the granulation equipment.

[0092] In one embodiment of the invention the granules are dried directly
in the granulation equipment which is a single pot processor.

[0093] In one embodiment of the invention the granules are dried using the
fluidized bed and the equipment is pre-heated before drying.

[0094] Process conditions for a commercial scale fluidized bed dryer (from
50 to 300 kg) are the following: inlet air temperature from 60° C.
to 110° C., for instance from 75° C. to 85° C.,
outlet air temperature at the end of drying from 25° C. to
60° C., for instance from 30° C. to 55° C., air flow
rate during drying from 1500 m3/h to 5000 m3/h, for instance
from 2500 m3/h to 4500 m3/h, drying time from 20 min to 200
min, for instance from 50 min to 170 min.

[0095] The temperature of the liquid within the jacket of a commercial
scale single pot processor (from 50 to 300 kg) may be from 30° C.
to 80° C., for instance from 35° C. to 60° C. The
drying time depends on the size of the equipment and on whether the
drying is assisted, for instance by one or more of the following: vacuum,
gas stripping, swinging bowl system and microwaves.

[0096] The inner temperature of a commercial scale a drying chamber may be
from 30° C. to 80° C., for instance from 35° C. to
55° C. The drying time depends on the size of the equipment and on
whether the drying is assisted.

[0097] In one embodiment of the invention the granulation is carried out
by melt granulation.

[0098] In the case of melt granulation the granules are cooled after the
granulation.

[0099] In one embodiment of the invention the granules are screened e.g.
in a rotating impeller, a rotating screen or an oscillating bar screening
mill.

[0100] In one embodiment granules are screened to the following granule
size distribution by volume: the 10% fractile is, for instance from 7
μm to 60 μm, for instance from 10 μm to 40 μm and the 90%
fractile is, for instance from 600 μm to 1200 μm, for instance from
750 μm to 1100 μm and the median is, for instance from 80 μm to
600 μm, for instance from 100 μm to 300 μm. The granule size
distribution by volume is measured using laser diffraction with dry
dispersion (Laser Diffraction Particle Size Analyzer LS13320, Beckman
Coulter Inc., USA). The analysis is carried out in ambient conditions.
The samples are dispersed in air using Tornado Dry Powder System. The
dispersion pressure is 19 inches H2O and the sample amount is 20 ml. The
percent values are calculated from the mean cumulative volume size curve
using the Beckman Coulter LS13320 software version 4.21.

[0101] In one embodiment of the invention one or more extragranular
excipients are brought into contact with the granules, for example by
diffusion blending (tumble), convection mixing or pneumatic mixing.

[0102] In one embodiment of the invention instead of blending the granules
with a lubricant the excipients facilitating the lubrication of the dies
of the tablet press are sprayed directly on the surfaces of the dies.

[0103] In one embodiment of the invention the granules (together with
optional extragranular excipients) are compressed into core tablets using
a tablet press whose feeding is based on gravity.

[0104] In one embodiment of the invention the granules (together with
optional extragranular excipients) are compressed into core tablets using
a power assisted or centrifugal tablet press.

[0105] In one embodiment of the invention, the core tablets prepared by
this method have the crushing strength from 70 N to and 220 N.

[0106] In one embodiment of the invention the core tablets are coated, for
instance with a cellulose derivative or polyvinyl alcohol based coating,
polyethylene glycols, acrylate polymers or sugar coating or mixtures
thereof. Preferably, a water based coating is used.

[0107] In one embodiment of the invention the coating comprises dyes,
colour lakes, or pigments, such as iron oxides, for instance yellow or
red irons oxides, and titanium dioxide.

[0108] In one embodiment of the invention the increase of the weight of
the tablet due to the application of the coating is, for instance from
0.5% to 10.0%, for instance from 1% to 4% by weight.

[0109] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with a
binder and a disintegrant and optionally one or more other excipients and
granulating with a granulating liquid (ii) drying and optionally
screening the granules of step (i), optionally bringing the granules into
contact with one or more extragranular excipients and (iii) compressing
the granules and the optional extragranular excipients into a core
tablet.

[0110] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with a
binder and a disintegrant and optionally one or more other excipients and
granulating with a granulating liquid (ii) drying and screening the
granules of step (i), optionally bringing the granules into contact with
one or more extragranular excipients and (iii) compressing the granules
and the optional extragranular excipients into a core tablet.

[0111] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with
povidone, croscarmellose sodium and optionally one or more other
excipients and granulating with water (ii) drying and screening the
granules of step (i), optionally bringing the granules into contact with
one or more extragranular excipients and (iii) compressing the granules
and the optional extragranular excipients into a core tablet.

[0112] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with
povidone, croscarmellose sodium and optionally one or more other
excipients and granulating with water, the amount of water added during
granulation being from 50% to 120% compared with the dry weight of the
granulation mass (ii) drying and screening the granules of step (i),
optionally bringing the granules into contact with one or more
extragranular excipients and (iii) compressing the granules and the
optional extragranular excipients into a core tablet.

[0113] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with
povidone, croscarmellose sodium microcrystalline cellulose; the
proportion of croscarmellose sodium to microcrystalline cellulose being
from 0.5:99.5 to 99.5:0.5 by weight; and optionally one or more other
excipients and granulating with water (ii) drying and screening the
granules of step (i), optionally bringing the granules into contact with
one or more extragranular excipients and (iii) compressing the granules
and the optional extragranular excipients into a core tablet.

[0114] In one embodiment of the invention a core tablet is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with
povidone, croscarmellose sodium microcrystalline cellulose; the
proportion of croscarmellose sodium to microcrystalline cellulose being
from 0.5:99.5 to 99.5:0.5 by weight; and optionally one or more other
excipients and granulating with water the amount of water added during
granulation being from 50% to 120% compared with the dry weight of the
granulation mass (ii) drying and screening the granules of step (i),
optionally bringing the granules into contact with one or more
extragranular excipients and (iii) compressing the granules and the
optional extragranular excipients into a core tablet.

[0115] In one embodiment of the invention granules are prepared by (i)
preparing a mixture of entacapone as the sole drug substance with a
binder and optionally one or more other excipients and granulating the
mixture with a granulating liquid or granulating entacapone together with
one or more optional other excipients with a granulating liquid
comprising a binder or by melt granulation; (ii) drying or cooling,
respectively and optionally screening the granules of step (i).

[0116] As it comes to steps (i) and (ii) above, conditions, excipients and
equipment etc. described in connection of the preparation of the core
tablet may be used.

[0117] In another embodiment of the invention a granule mixture is
prepared by (i) preparing a mixture of entacapone as the sole drug
substance with a binder and optionally one or more other excipients and
granulating the mixture with a granulating liquid or granulating
entacapone together with one or more optional other excipients with a
granulating liquid comprising a binder or by melt granulation; (ii)
drying or cooling, respectively and optionally screening the granules of
step (i), bringing the granules into contact with one or more
extragranular excipients.

[0118] As it comes to steps (i) and (ii) above, conditions, excipients and
equipment etc. described above in connection of the preparation of the
core tablet may be used.

[0119] In one embodiment of the invention a capsule is prepared by (i)
preparing a mixture of entacapone as the sole drug substance with a
binder and optionally one or more other excipients and granulating the
mixture with a granulating liquid or granulating entacapone together with
one or more optional other excipients with a granulating liquid
comprising a binder or by melt granulation; (ii) drying or cooling,
respectively and optionally screening the granules of step and (i)
optionally bringing the granules into contact with one or more
extragranular excipients and (iii) filling the granules and optional
extragranular excipients into a suitable capsule.

[0120] As it comes to steps (i) and (ii) above, conditions, excipients and
equipment etc. described above in connection of the preparation of the
core tablet may be used.

[0121] In one embodiment of the invention the size of a hard gelatine
capsule is used having a shell size from 2 to 00, for instance from 1 to
0 in the preparation of the capsule. The weight of a capsule shell of
this size is typically from 60 mg to 125 mg.

[0123] The term "polyvinyl alcohol based coating" encompasses the tablet
coating-films in which the polyvinyl alcohol (Airvol, Elvanol, Gohsenol)
is used as the film-forming agent.

[0124] The term "cooling" encompasses active cooling or allowing cool to
the ambient temperature.

[0125] The term "melt granulation" encompasses a size enlargement process
where fine powder feed particles are bound together by a process where
the binder is added as a solid and mixed with the powder while the
granulator temperature is raised above the melting point of the binder or
the melted binder is sprayed on the powder in a fluidized bed granulator.

[0126] The term "granule mixture" encompasses the mixture of the granules
according to the invention with one or more extragranular excipients
including granules and powders.

[0127] The term "fractionating" encompasses any conventional method which
sorts the particles according to their size, such as sieving method or
air fractionating method.

[0128] As a general textbook reference on providing more information of
the excipients mentioned herein a reference is made to Handbook of
Pharmaceutical Excipients, Ed. Rowe R. et al. Pharmaceutical Press,
American Pharmaceutical Association, Fourth edition, 2003.

[0129] Entacapone may be prepared, for instance by the methods described
U.S. Pat. No. 5,446,194 and U.S. Pat. No. 5,135,950, which are
incorporated herein by reference. Entacapone may exist as any mixture of
(E)- and (Z) isomers or in a form of a substantially pure (E)- or (Z)
isomer. Preferably, entacapone is in a substantially pure (E)-isomeric
form. The (E)-isomer may take different polymorphic forms, e.g. polymorph
A disclosed in U.S. Pat. No. 5,135,950 or polymorph D disclosed in patent
application No. WO 2005/063696.

[0130] Also different salts having comparable dissolution properties to
that of entacapone may be used instead of free entacapone, i.e. salts
having an intrinsic dissolution rate comparable to entacapone in
discriminative test conditions. Intrinsic dissolution rate is defined as
dissolution rate of pure substances under the condition of constant
surface area. The intrinsic dissolution rate is determined by exposing
the constant surface area of material to an appropriate dissolution
medium while maintaining constant temperature, stirring rate, and pH
(phosphate buffer, 37° C., 50 rpm, pH 5.5 in this case).

[0131] Entacapone (or its salt, respectively) having the particle size
distribution defined above can be provided in several ways, for instance
by reducing the particle size of entacapone particles obtained from the
compound synthesis, for instance mechanically by milling (for example by
a bal mill, a fluid energy attrition mill or a jet mil), by ultrasonic
means and/or by fractionating or by crystallizing it directly to the
desired particle size.

[0132] As a general textbook reference on providing particles of desired
size as well as to manufacturing technologies mentioned herein a
reference is made to Remington's Pharmaceutical Sciences, 18th ed,
1990, Mack Publishing Company, Easton, Pa. 18042. Suitable manufacturing
technologies may be also found in Pharmaceutics the Science of Dosage
Form Design Ed. M. E. Aulton, 2000.

[0133] In order to be effective, for example in the treatment of
Parkinson's disease or Restless Legs Syndrome each dosage form according
to the invention is to be taken sequentially or simultaneously with a
dopamine precursor (such as levodopa or ethyl ester of levodopa) and a
DDC inhibitor and optional other drug substances.

[0134] The pharmacologically effective amounts of entacapone, levodopa and
the DDC inhibitor are dependent on numerous factors known to those
skilled in the art, such as, the type and the severity of the condition
of the patient, the highest recommended daily dose being 200 mg of
entacapone ten times a day (i.e. 2000 mg entacapone per day). For
example, in the treatment of RLS the daily dose of levodopa can be as low
as 50 mg, for example from 50 mg to 300 mg but can be from 200 mg to 600
mg, divided into 1 to 4, preferable into 1 to 2 individual doses, whereas
in the treatment of severely ill Parkinsonian patients the daily dose of
levodopa can be considerably higher, for example from 100 mg to 2000 mg
divided, for example from two to ten individual doses.

[0135] The amount of entacapone in a single dosage unit according to the
invention is, for instance from 100 mg to 400 mg, e.g. from 100 mg to 300
mg, especially from 100 mg to 200 mg. The amount of levodopa in a single
dosage unit is, for instance from 50 mg to 400 mg, e.g. from 50 mg to 300
mg, for example from 50 mg to 200 mg.

[0136] DDC inhibitors include, without limitation, carbidopa and
benserazide. Levodopa and carbidopa are commercially available both as
immediate release and slow release (depot) combination tablets sold in
Europe under, for instance, the following trademarks: Nacom®,
Sinemet®, Sinemet Depot® and Sinemet® Plus. Levodopa and
benserazide are commercially available both as immediate release and slow
release (depot) combination tablets, for instance, under the trademark
Madopar® and Rextex®.

[0137] The amount of carbidopa in a single dosage unit is, for instance
from 5 mg to 200 mg, e.g. from 5 mg to 100 mg, e.g. from 5 mg to 50 mg.

[0138] DDC inhibitor and levodopa (or other dopamine precursor) are
administered, for example in a ratio of from 1:1 to 1:40, for example
from 1:4 to 1:10.

[0139] The MAO B inhibitors include, without limitation selegiline,
rasagiline, lazabemide and safinamide. The daily dose of selegiline is
from 1 to 20 mg, for example from 2 to 10 mg, divided into 1 to 10,
preferably into 1 to 2 individual doses. The daily dose of rasagiline is
from 0.1 to 5.0 mg, for instance from 0.5 to 2 mg divided into 1 to 10,
preferably into 1 to 2 individual doses. The daily dose of lazabemide is
from 100 to 800 mg, for instance from 100 to 200 mg divided into 1 to 10,
preferably into 1 to 2 individual doses. The daily dose of safinamide is
from 10 to 600 mg, for instance from 50 to 150 mg divided into 1 to 10,
preferably into 1 to 2 individual doses.

[0140] The invention will be further clarified by the following
non-limiting examples.

[0142] Entacapone having at least 90% of the particles less than 30 μm
and not more than 20% of the particles less than 3 μm was obtained by
milling with a fluid energy mill (an opposed jet type with a dynamic
classifier).

[0145] The mass is finalized by adding magnesium stearate (distributed by
Mallinckrodt Chemical Limited) to the granules and mixing for 5 min
(Turbula T10B).

[0146] Tablets are compressed with a rotary tablet press (Fette P I) by
using compression force of approx 7 kN and tabletting speed of approx. 16
000 tablets/h. Core tablets are coated with a PVA-based film (distributed
by Colorcon under trademark Opadry®) in a coating drum (Accela-Cota
24'').

[0148] Especially good quality to the product can be achieved with
compositions 2 to 4, with which the tablet disintegration and flowability
of the tabletting mass can be improved. Increased flowability decreases
the weight variation of the tablets, which can be seen in improved
content uniformity. Also, no lamination is observed with said
formulations in spite of the high amount of croscarmellose sodium.

[0151] Povidone is dissolved in purified water (compositions 5 and 6)
forming a solution with concentration of approx. 6% w/w. The granulation
liquid (purified water or povidone solution) is sprayed to the pre-mixed
powder blend.

[0152] Granules are dried in a drying chamber (Memmert), or most
preferably in a single pot processor and screened with a conical mill
(Glatt GS 100, mesh size of friction screen 1.3 mm). The mass is
finalized by adding magnesium stearate (distributed by Mallinckrodt
Chemical Limited) and possible colloidal silica (distributed by Algol
Chemicals Oy under trademark Aerosil® 200) to the granules and mixing
for 5 min (Turbula T10B).

[0154] Core tablets are coated with a PVA-based film (distributed by
Colorcon under trademark Opadry®) in a coating drum (Accela-Cota
24'').

[0155] Tablets with good technical properties are achieved with
composition 5 described above. The flowability of the mass, and thus the
processability of the product, can be improved with extra-granular
colloidal silica (composition 7). Even better flowability can be achieved
with composition 6.

[0159] The mass is finalized by adding a proper amount of maize starch
(distributed by Cerestar Scandinavia A/S) to adjust the volume of the
mass to fit to capsule shell no. 0 and magnesium stearate (distributed by
Mallinckrodt Chemical Limited) or sodium starch glycolate (a
disintegrant), respectively, to the granules and mixing for 5 min
(Turbula T10B).

[0161] Entacapone and PEG 3000 are mixed with a spatula in a decanter.
Thereafter the mixture is hot melt granulated on a heating plate. The
granules are screened through a 1.5 mm screen. Capsule shells No. 0 are
filled with granules by weight.

[0165] The mass is finalized by adding magnesium stearate (distributed by
Mallinckrodt Chemical Limited) to the granules and mixing for 5 min
(Turbula T10B).

[0166] Tablets are compressed with a rotary tablet press (Fette P I) by
using compression force of approx 13 kN and tabletting speed of approx.
16 000 tablets/h. Core tablets are coated with a PVA-based film
(distributed by Colorcon under trademark Opadry®) in a coating drum
(Accela-Cota 24'').

Patent applications by Kari Vahervuo, Espoo FI

Patent applications by Orion Corporation

Patent applications in class C=O other than as ketone or aldehyde

Patent applications in all subclasses C=O other than as ketone or aldehyde